Advancing Genomics Of Recessive Ataxias Project summary Hereditary spastic paraplegias have a heterogeneous genetic etiology. While ~50% of all patients of dominant HSP are explained by three major genes (spastin, atlastin, REEP1), the remaining genetic causes are rare and explain no more then another 15% of patients. For recessive HSP only about 40-50% of patients receive a genetic diagnosis. Recent progress is tremendous and will likely identify the genetic basis for another 20% of patients in the coming five years. Especially interesting is that less than 50% of cases are clarified in select exome sequencing approaches, implaying that whole genome studies will be necessary. In addition, HSPs often show clinical overlap with related neurological diseases, such as ataxias, leukodystrophies, metabolic disorders, and mitochondrial disorders. Thus, there is a two-fold need: 1) to standardize the clinical classification in a collaborative fashion and 2) to expand the knowledge of underlying causative genes and molecular pathways. This will be beneficial beyond HSP and contribute to our understanding of a number of related neurological diseases. For this study, we will create a collaborative structure between investigators in the USA, Germany, France, Belgium, Brazil, Austarlia, and indirectly Middle East and Northern Africa. We will be able to systematically study THE largest clinical sample of HSP in the world led by world-renowned clinical and genetic experts. Importantly, existing genomic data will be contributed in kind by our collaborators and jointly used in the analysis. Our recent success in identifying dozens of genes for familial neurological disorders, including HSP validates the suggested approach. Data will be shared with dbGAP. We expect to identify and publish 2 ? 4 novel genes per year and create a lasting resource of clinical and genomic data.